Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-(Phosphonacetyl)-L-aspartic acid, an inhibitor of aspartate transcarbamylase, was administered to 25 patients with advanced cancer by 10-minute infusion daily x 5 consecutive days to determine the toxicity and to look for evidence of therapeutic effect. Planned dose escalations ranged from 100 to 1250 mg/m2 (daily dose). Nausea, vomiting, and diarrhea were the most frequent toxic effects, with three of six patients treated at a daily dose of 1250 mg/m2 having severe diarrhea. Other toxic effects were encountered rarely and were not dose-limiting; these included mild leukopenia, thrombocytopenia, rash, stomatitis, and increases in SGOT. One patient with a widely metastatic carcinoid of unknown origin had an objective response lasting 6 weeks.
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PMID:Phase I study of N-(phosphonacetyl)-L-aspartic acid (PALA). 52 23

5-Fluorouracil (FUra) is a clinically useful antineoplastic agent. Preclinical studies suggest that the therapeutic effects of FUra can be enhanced by pretreatment with N-(phosphonacetyl)-L-aspartic acid (PALA), an inhibitor of aspartate transcarbamylase. The objective of treatment with PALA is to increase the activation of FUra by inhibiting the normal pathway of de novo pyrimidine biosynthesis. Theoretically, the optimal dose of PALA should produce effective blockade of this pathway without increasing toxic effects of FUra. Using pyrazofurin-induced orotic aciduria and orotidinuria as a measure of this pathway, it as determined that PALA (250 mg/sq m) is effective in inhibiting total-body pyrimidine synthesis. Sixty-eight adult patients with cancer were treated with combinations of PALA and FUra. High doses of PALA (1 to 2 g/sq m) prevented the use of full dosage of FUra; however, PALA (250 mg/sq m) can be administered 24 hr before FUra (750 mg/sq m) once weekly for at least 3 weeks. The toxicity observed using that combination of doses was mild to moderate myelosuppression, mucositis, diarrhea, nausea, and vomiting. Further clinical studies are warranted.
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PMID:Phase I and clinical pharmacological evaluation of biochemical modulation of 5-fluorouracil with N-(phosphonacetyl)-L-aspartic acid. 683 57

The biochemical modulators PALA, an inhibitor of aspartate transcarbamylase which depletes uridine nucleotide pools, and 6-methylmercaptopurine riboside (MMPR) which inhibits purine metabolism, selectively potentiate the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Based on a phase I trial of this combination, we performed a phase II trial in patients with advanced pancreatic cancer. PALA 250 mg/m2 was administered i.v. on day 1, followed 24h later by MMPR 150 mg/m2 as a bolus i.v. injection, and 5-FU 2300 mg/m2 by 24h infusion. Treatments were repeated weekly. Seventeen patients, all previously untreated with chemotherapy, were entered, of whom 14 are evaluable for response. Toxicity > or = grade 2 included nausea (6/17), vomiting (4/17), diarrhea (3/17), stomatitis (5/17), and neurotoxicity (2/17). Among 14 evaluable patients there were no partial responses, and two patients with stable disease. Pretreatment with PALA and MMPR is insufficient to enhance the activity of 5-FU in pancreatic cancer.
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PMID:Phase II trial of PALA and 6-methylmercaptopurine riboside (MMPR) in combination with 5-fluorouracil in advanced pancreatic cancer. 777 33